Neuroregeneration

1
Neuroregeneration
Bear M. F., Connors B. W. Paradiso M. A.
Neuroscience. Exploring the brain 2007, 3d ed.
Lippincott Williams and Wilkins
2
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

3
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

4
Terminology

• NEURODEGENERATION

The loss of neuronal processes (axons and
dendrites) and death of nerve cells

• NEURODEGENERATIVE DISORDER

A type of neurological disease marked by the loss
of nerve cells e.g. Alzheimers disease (AD),
Parkinsons disease PD), Huntingtons disease (HD)

• REGENERATION

• Growth anew of lost tissue or destroyed parts or
  organs

• NEUROREGENERATION

• Regeneration of the nervous tissue manifested by
• Nerve (axon) regeneration
• Neural stem-cell proliferation, migration and
  differentiation

5
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

6
Axon regeneration

• Traumatic injury of the spinal cord that
  transects axon processes
• results in permanent functional impairment,
  even when the neuronal
• cell bodies that are located away from the
  injury site remain alive.

• At present there are no clinical treatments
  available to stimulate
• regeneration of cut axons within the CNS.

• Although many CNS neurons can survive for years
  after axotomy, the
• severed axons ultimately fail to regenerate
  beyond the lesion site, in
• contrast to those in the PNS or embryonic
  nervous system.

• Spinal cord injured patients receive high doses
  of the steroid
• methylprednisolone immediately following
  injury to suppress an
• unfavorable inflammatory reaction. This drug,
  however, does not
• restore functions that are lost when axons are
  cut.

7
Changes in CNS environment after maturation and
injury
8
Schematic representation of CNS injury site
9
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

10
Inhibitors of axon regeneration
Growth inhibitory activity associated with myelin

• Myelin-associated glycoprotein (MAG)

• Growth inhibitory protein Nogo

• Oligodendrocyte-myelin glycoprotein (OMgp)

• Oligodendrocyte-proteoglycan NG2

Growth inhibitory activity present at the glial
scar

• Chondroitin sulfate proteoglycans (CSPG)
• - versican
• - phosphocan
• - neurocan

Other factors limiting axon-regrowth

• Inflammatory response

• Alterations in the ECM

• Upregulation of semaphorins, ephrins, tenascin-C

11
Glial inhibitors
12
Neurotrophins and their receptors
The neurotrophins are secreted proteins, growth
factors, required by discrete neuronal cell type
for survival and maintenance, with a broad range
of activities in CNS and PNS in the developing
and adult animal.
The complete family of mammalian neurotrophins
consists of the nerve growth factor (NGF),
brain-derived neurotrophic factor
(BDNF), neurotrophin-3 (NT3) and neurotrophin-4/5
(NT4/5).
NGF was the first polypeptide growth factor
identified (Cohen Levi-Montalcini, 1956) and has
become a paradigm for trophic factor research.
BDNF was identified much later (Baeder et al.,
1982) and NT3 and NT4/5 were only cloned in 2000.
Following their initial characterization as
survival factor, it became clear that
neurotrophins do more than regulate the size of
distinct neuronal populations during development.
They have been shown to modulate processes as
diverse as cell migration, elaboration of
neurite, synaptic transmittion and
differentiation in neuronal and
non-neuronal cells.
13
Neurotrophins can counteract glial inhibitors
When receptors are expressed on their own, Trk
bind mature NTs preferentially, whereas p75NTR
binds all mature NTs with the same affinity. When
co-expressed, Trk and p75NTR form high-affinity
binding sites with increased ligand specificity.
14
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

15
Strategies to promote axon regeneration
1. Neutralization of the inhibitory factors in
the injured CNS
- Ab infusion (MonAb, IN-1, against Nogo-A )
- A therapeutic vaccine approach
- Passive immunization at the time of lesion
- Antagonist peptide (Nogo-66 NEP1-40 peptide)
- Inhibition of Rho signaling (Y-27632, an
inhibitor of p160ROCK)
- Inhibiting CSPG (Chondroitinase ABC)
- Anti-scarring treatment (inhibition of
fibroblast proliferation)
2. Stimulation of axon regeneration by modulating
the neuronal signaling responses
- Treatment with neurotrophic factors (NGF,
BDNF, NT-3, GDNF, LIF, FGF-2)
3. Cell transplantation e.g. Schwann cells,
fibroblasts modified to express trophic
factors, fetal spinal cord transplants,
embryonic stem cells etc.
16
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

17
Neural stem cells
Neurodegenerative disorders (AD, PD and HD)
are characterized by continuous loss of
neurons that are not replaced. It is
postulated that a primary deficit in neural cell
proliferation, migration and differentiation
might contribute to net cell loss and neuronal
circuit disruption in these disorders.
18
Neural stem cells
Ventricular and subventricular zones in the wall
of the lateral ventricle adjacent to the
caudate-putamen
Subgranular zone of the hippocampus
NSC
Migration of NSC
Olfactory bulb
Differentiation Integration
NSC
Neurons Dentate gyrus
NPC
Differentiation
Local interneurons
19
Neural stem cells niches
The SVZ niche, cell types and stem cell lineage
The DG neurogenic niche, cell types and lineage
SVZ, subventricular zone DG, dentate gyrus LV,
lateral ventricle BL, specialized basal lamina
BV, blood vessels A (red), neuroblasts B
(blue), neural stem cells (SVZ astrocytes) C
(green), transit rapidly amplifying cells D
(yellow), precursors G (red), neurons
20
Stem and progenitor cells of the adult human brain
The human temporal lobe it includes
periventricular neural stem cells (red) that
generate at least three populations of
potentially neurogenic transit amplifying
progenitors of both neuronal and glial lineages
(yellow). These include the neuronal progenitor
cells of the ventricular subependyma, those of
the SGZ of the dentate gyrus, and the glial
progenitor cells of the subcortical white
matter. Each transit amplifying pool may then
give rise to differentiated progeny appropriate
to their locations, including neurons (purple),
oligodendrocytes (green), and parenchymal
astrocytes (blue).
21
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

22
Parkinsons disease
(degenerative disorder of the CNS that often
impairs the sufferer's motor skills and speech)
PD patient (sketch, 1886)
Muscle rigidity, tremor (bradykinesia)
Treatment L-DOPA ( dyskinesia involuntary
movements)
PET scan, dopamine activity in basal ganglia,
putamen and caudate
23
General developmental pathway of dopamine neurons
24
Alternative sources of stem cells for
transplantation in PD
25
Present limitations in the development of the
hESC-based therapy for PD
26
Generation of dopamine neurons from autologous
human mesenchimal stem cells (MSCs)
27
Summary
Neural degeneration in the central nervous system
is manifested by the loss of neuronal processes
(axons and dendrites) and death of nerve cells
resulting in dysfunctional plasticity and
cognitive impairment.
Traumatic injury of the spinal cord that
transects neuronal processes results in permanent
functional impairment, even when the neuronal
cell bodies that allocated away from the injury
site remain alive. Mounting evidence suggests
that the glial environment in the adult CNS,
which includes inhibitory molecules in CNS myelin
as well as proteoglycans associated with
astroglial scaring, might present a major hurdle
for successful axon regeneration.
Therefore, targeting the inhibitory components of
the adult glial environment might not only
promote the regeneration of the damaged nerve
fibers but also enhance axon sprouting and
plasticity after CNS injury.
Neural stem cells, able to self renew and give
rise to both neurons and glia, line the cerebral
ventricles of the adult human brain. These
various stem and progenitor cell types may
provide targets for pharmacotherapy for a variety
of disorders of the central nervous system. Each
resident progenitor type may be immortalized and
induced to differentiate in vivo by the actions
of both exogenous factors and small molecule,
modulators of progenitor selective signaling
pathways.
This strategy may be particularly efficacious in
neurodegeneration such asParkinsons disease, in
which lost neurons may be replenished through the
directed induction of progenitor cells lining the
ventricular wall of the affected striatum. Recent
advances in stem cell research give a hope that
stem cell transplantation to replace the
degenerated neurons may be a promising therapy
for PD. There are three sources of stem cells
currently in testing embryonic stem cell, neural
stem cells and mesenchymal stem cells. Future
stem cell research should focus not only on
ameliorating the symptoms of PD, but also
on neuroprotection or neural rescue that can
favorably modify the natural course and slow the
progression of the disease.
28
Helpful reading
Wang Y et al. (2007) Stem cell transplantation A
promising therapy for Parkinsons disease. J
Neuroimmune Pharmacol. 2243-250. Goldman SA
(2007) Disease targets and strategies for the
therapeutic modulation of endogenous neural stem
and progenitor cells. Clin Pharm Therapeutics.
82453-460. Ma QH et al. (2007) Physiological
role of neurite outgrowth inhibitors
in myelinated axons of the central nervous
system implications for the therapeutic
neutralization on neurite outgrowth
inhibitors. Curr Pharm Des. 132529-2537.
Trzaska KA et al. (2007) Current advances in the
treatment of Parkinson's disease with stem
cells. Curr Neurovasc Res. 499-109. Yiu G
et al. (2006) Glial inhibition of CNS axon
regeneration. Nat Rev Neurosci. 7617-627.
Correia AS et al. (2005) Stem cell-based therapy
for Parkinson's disease. Ann Med. 37487-498.
Doetsch F (2003) A niche for adult neural stem
cells Curr Opin Gen Dev. 13543-550.